Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread worldwide and to produce severe and sometimes fatal lung infections characterized by severe pneumonia and marked alveolar damage. Evidence accumulating over the past several decades strongly suggest that disease produced by IAV infection not only reflects the extent of virus replication in the respiratory tract but als the strength or magnitude of the host innate and adaptive immune response. Our laboratory has had a long-standing interest (over 30 years duration) in understanding the role of the innate and adaptive immune response in IAV clearance from the infected lungs and in the development of associated pulmonary inflammation and injury. The foundation of this exploratory R21 application is a set of recent fortuitous findings implicating leptin/leptin receptor signaling in he IAV infected lungs as an important regulator of the extent of pulmonary inflammation and injury and therefore the severity of IAV infection. This application is designed to obtain critical additional data both in an experimental (murine) model and by inference in the human via SNP analysis which is necessary for a future more detailed analysis of leptin/leptin receptor signaling in IAV infection. To this end we propose the following Specific Aims: 1.To establish the contribution of Leptin and Leptin Receptor signaling to the severity and outcome of IAV infection and to identify the cellular target(s) of Leptin action in the infected lungs;2.To identify the Lepin Receptor signaling pathway(s) mediating the disease promoting enhanced host response following IAV infection. The successful completion of the proposed analysis offers the possibility of novel therapeutic strategies to ameliorate the severity of IAV infection.